Chronic interstitial lung disease is observed in a variety of disorders, including infectious diseases, autoimmune disorders of connective tissue, and disorders where the etiology is unknown, such as idiopathic pulmonary fibrosis. While the etiology and mechanism of progression of many of these lung disorders are not known, the exacerbated progression of the disease may be dictated by the host responding to a subsequent pathogen superimposed on the initial etiologic agent. This second hit triggers a dynamic interaction in the lung between the inciting agent, immune cells, and structural cells of the lung, culminating in fibroblast activation, proliferation and fibrosis. Understanding the mechanisms responsible for the exacerbation and progression of lung disease chronicity and fibrosis are the broad, long-term objectives of this application. We hypothesize that the host's response to a persistent etiologic agent may predispose lung tissue to an environment of reparative and immunoregulatory cytokines, placing the lungs at risk for a viral infection, which mechanistically contributes to disease chronicity by maintaining a unique cytokine phenotype, altering dendritic cell function, and driving fibroblast activation. We have designed experiments to test this hypothesis and determine if the progression and maintenance of chronic lung inflammation are infuenced by the cytokine phenotype and the host's response to a subsequent viral pathogen superimposed on the initial etiologic agent, constituting a two hit mechanism for disease progression. We will focus on mechanisms which lead to a minimally fibrotic lung lesion, induced by type 1 cytokines, versus a fibrotic response, induced by type 2 cytokines, and determine their impact on a subsequent challenging with murine gammaherpesvirus (MHV68). Our specific Aims include: 1) To assess the mechanism(s) whereby MHV68 infection alone or superimposed on a polarized cytokine phenotype alters the host response and subsequent lung pathology in experimental models of chronic lung inflammation; 2) To determine the mechanistic contribution of an MHV68-derived gene product on the evolving chronic lung pathology associated with a type 1 or type 2 cytokine tissue phenotype; and 3) To assess the mechanistic contribution of dendritic cell subsets during MHV68 infection to the chronicity and fibrosis of the lung response in animals with developing type 1 or type 2 cytokine phenotypes.